Long-term safety and efficacy of formoterol fumarate inhalation solution in patients with moderate-to-severe COPD

Abstract

Background

Formoterol fumarate inhalation solution (FFIS; Perforomist^®) is a long-acting β₂-agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was <1.5. Secondary end points included spirometry.

Results

The planned 1-year treatment period was completed by 520 patients; 551 discontinued prematurely (FFIS: 45.7%; placebo: 57.4%). The median treatment duration was approximately 10 and 7 months for FFIS and placebo, respectively. Among 1,071 randomized patients, 121 had ≥1 primary event (FFIS: 11.8%; placebo: 10.8%). The estimated HR of a primary event with FFIS vs placebo was 0.965 (90% CI: 0.711, 1.308), demonstrating that FFIS was noninferior to placebo. No respiratory deaths were observed in the FFIS group. Adverse events were similar for FFIS vs placebo (patients with ≥1 treatment-emergent adverse events: 374 [69.1%] vs 369 [69.6%], respectively). Compared with placebo, FFIS demonstrated statistically greater improvements from baseline in trough FEV₁, FVC, percent predicted FEV₁, and patient-reported outcomes (Transition Dyspnea Index).

Conclusions

Nebulized FFIS was noninferior to placebo with respect to safety in patients with moderate-to-severe COPD. Additionally, fewer treatment withdrawals and larger lung function improvements were observed with FFIS compared with placebo when added to other maintenance COPD therapies.

Keywords:

• COPD
• safety
• bronchodilators
• long-acting beta2-agonists
• nebulization

Supplementary materials

Ethical review boards participating in the clinical trial

Three ethical review boards were used for the trial. All investigator sites used a Central Institutional Review Board (New England Institutional Review Board [NEIRB]) except for three sites, which used their local institutional review board (IRB).

The details of the IRBs are as follows:

Table S1 Central IRB

Table S2 Local IRBs

Acknowledgments

Mylan Inc. (Canonsburg, PA, USA) funded both the study and medical writing support. The authors acknowledge Roger Hill, PhD, for medical writing and Paula Stuckart for editorial assistance in the preparation of the manuscript (Ashfield Healthcare Communications, Middletown, CT, USA). The abstract of this paper was presented at the 2017 CHEST Annual Meeting and the 2017 American Thoracic Society conference as an oral and poster presentation, respectively, with interim findings. The poster’s abstract was published as “Poster Abstracts” in CHEST, 2017;152(4):Suppl A769, https://doi.org/10.1016/j.chest.2017.08.800 and Am J Respir Crit Care Med. 2017;195:A5473, https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A5473.

Disclosure

NAH received fees as a consultant or serving on advisory board from Roche/Genentech, Novartis, Boehringer Ingelheim, Mylan, and AstraZeneca and grant support from GlaxoSmith-Kline, Mylan, Boehringer Ingelheim, and Roche/Genentech. SS received research support from AstraZeneca and Mylan; he was on advisory committees, a consultant, and/or a speaker for Aradigm, AstraZeneca, Bayer Schering Pharma, Boehringer Ingelheim, Cempra, CSL, Behring, GlaxoSmithKline, Merck, Invacare, Pulmonx, Sunovion, and Theravance Biopharma. AK is an employee of Mylan Inc., USA. JKW, JS, and DN are employees of Mylan Pharma UK Ltd. The authors report no other conflicts of interest in this work.